This invention is in the field of clinical neurology and relates specifically to compound, formulations and methods for use in improving implicit memory, particularly in patients afflicted with or susceptible to Alzheimer""s Disease.
L-Glutamate is one of the major excitatory neurotransmitters in the central nervous system. Over the past decade, evidence has been accruing that the N-methyl-D-aspartate (NMDA) subtype of glutamate receptor is involved in processes of learning and memory [J. B. Monahan et al, Pharmacology, Biochemistry and Behavior, 34, 649-653(1989)]. As a result, the NMDA receptor complex has become a target site for the development of pharmacological agents to treat memory disorders associated with aging and dementia.
One concern in the development of therapeutic agents is that agents potentiating NMDA-type glutamate activity can overstimulate neurons, which leads to excitotoxity and eventual cell death. However, the recent discovery of the glycine-B site on the NMDA receptor complex has provided an avenue for drugs to modulate glutamate activity [N. W. Kleckner et al, Science, 241, 835-837 (1988)]. In the presence of glutamate, glycine increases the likelihood that glutamate will be effective in promoting channel opening allowing positively charged ions to flow into the nerve cell, thereby exciting the cell. One drug that acts at the glycine modulatory site is the partial glycine agonist D-cycloserine [W. F. Hood et al, Neuroscience Letters, 98, 91-95 (1989)]. At xe2x80x9clowxe2x80x9d concentrations, D-cycloserine behaves as an agonist mimicking glycine""s effects, whereas at xe2x80x9chigherxe2x80x9d concentrations it can antagonize the effects of endogenous glycine. The antagonist property of D-cycloserine can prevent excess stimulation of the neuron, thereby preventing excitotoxicity.
Recent findings have shown that D-cycloserine ameliorates learning and memory deficits associated with normal aging [M. G. Baxter et al, Neurobiology of Aging, 15, 297-213 (1994)] and drug-induced amnesia [R. W. Jones et al, Annals of the New York Academy of Science, 640, 241-244 (1991)]. These findings are of particular importance to the treatment of memory disturbances found in Alzheimer""s disease [K. Wesnes et al, Human Psychopharmacology, 3, 27-41 (1988)]. For instance, administration of scopolamine, a cholinergic blocker, to healthy human subjects produces reversible memory deficits that resemble those found in Alzheimer""s disease [K. Wesnes et al, Ibid.]. D-cycloserine has been shown to alleviate a variety of scopolamine-induced deficits for recently presented items [R. W. Jones et al, Ibid.]. For example, D-cycloserine can improve deficient recall and recognition performance in young adults and recognition performance in older adults [R. W. Jones et al, Ibid.]. 
It has been shown that the compound milacemide, acting at the glycine site, facilitates word retrieval in healthy young and older adults [B. L. Schwartz et al, Neurology, 41, 1341-1343 (1991)].
Amino-oxazolidone compounds have been investigated for CNS effects. For example, the compound D-cycloserine, in its D- and L-isomer forms, has been evaluated for CNS effects in animals [0. Mayer et al, Arzneim. Forsch., 21(2), 298-303 (1971)]. These cycloserine isomers have also been evaluated for psychological and physiological effects in human subjects. For example, D-cycloserine when administered at 500 mg/day doses to healthy human subjects, appeared to stimulate slight sociability, but with depressed mental alertness [M. Vojtechovsky, Act. Nerv. Super., 7(3), 269 (1965)]. Also, D-cyloserine has been administered at 1000 to 1500 mg/day to healthy volunteers whose blood levels showed increased levels of monoamine oxidase enzyme activity [V. Vitek et al, Psychopharmacologia, 7(3), 203-219 (1965)].
D-cycloserine has been investigated as a therapeutic agent for mental disorders in clinical trials, wherein D-cycloserine was administered to mentally disturbed patients at doses of 500 mg per day [G. E. Crane, Compr. Psychiat., 2, 51-53 (1961)]. In such clinical trials, improvements in depression, insomnia, anexoria or tension were found for some patients, while patients suffering from severe neurosis or psychosis responded poorly to such medication. Moreover, D-cycloserine has been used to exacerbate the symptoms of schizophrenia in an attempt to cure the ailment by symptom provocation [J. Simeon et al, Compr. Psychiat., 11, 80-88 (1970)]. It appears that D-cycloserine, at the dose levels used in these studies, is acting as an antagonist at the glycine site of the NMDA-PCP receptor complex mimicking the action of PCP by inducing psychosis.
Other CNS-related investigations have been conducted with amino-oxazolidone compounds for interactions with the NMDA receptor complex. For example, U.S. Pat. No. 4,904,681 issued on Feb. 27, 1990 to A. A. Cordi et al describes evaluation of D-cycloserine as a glycine B partial agonist interacting with the NMDA receptor complex for treatment of learning or memory dysfunctions or for enhancement of cognitive functions. U.S. Pat. No. 5,061,721 issued on Oct. 29, 1991 to A. A. Cordi et al describes methods of treating Alzheimer""s Disease, age-associated memory impairment, learning deficit and psychotic disorders, as well as methods for improving memory or learning in healthy subjects, using a composition containing a mixture of D-cycloserine and D-alanine. U.S. Pat. No. 5,087,633 issued on Feb. 11, 1992 to A. A. Cordi et al describes use of a glycine B partial agonist for memory and learning enhancement or treatment of a cognitive disorder. U.S. Pat. No. 5,187,171 issued on Feb. 16, 1993 to A. A. Cordi describes D-cycloserine as a glycine B partial agonist interacting with the NMDA receptor complex for treatment of psychotic conditions. U.S. Pat. No. 5,260,324 issued on Nov. 9, 1993 to A. A. Cordi et al describes compositions containing D-cycloserine with a side-effecting reducing amount of D-alanine, in a ratio range of about 1-to-1 to about 100-to-1 of D-alanine to D-cycloserine, for use in learning-memory enhancement or treatment of a cognitive psychotic disorder. U.S. patent application Ser. No. 08/155,986 filed on Nov. 22, 1993 of M. Nevins describes use of D-cycloserine for treatment of anxiety.